Diagnosis and rescue of malignant hyperthermia induced by anesthesia during radical surgery in a cervical cancer patient using the National Remote Emergency System: A case report.

RATIONALE: Malignant hyperthermia (MH) is a rare yet serious medical complication that typically arises following general anesthesia or the administration of specific anesthetics. Due to the infrequency of MH, anesthesiologists often lack sufficient expertise in identifying and managing it, leading to misdiagnosis and inappropriate treatment. There is an urgent need to enhance the diagnosis and management of MH through the utilization of relevant tools. PATIENT CONCERNS: In this case, a 52-year-old woman underwent radical cervical cancer surgery under general anesthesia, with no family or significant medical history. She experienced a gradual increase in end-tidal carbon dioxide (ETCO2) to a maximum of 75 mm Hg and a rise in body temperature from 36.5 to 37.5 °C in a very short period, as well as a blood gas analysis showing a pH of 7.217. DIAGNOSIS: The anesthesiologist immediately used The WeChat applet-based National Remote Emergency System for Malignant Hyperthermia (MH-NRES), and the score was 40, which indicated that the patient was very likely to have MH. INTERVENTIONS: We immediately discontinued sevoflurane and switched total intravenous anesthesia to maintain general anesthesia, with a rapid intravenous infusion of dantrolene sodium. OUTCOMES: The ETCO2 and the temperature quickly dropped to normal, followed by successful completion of the surgery, and the patient was discharged 8 days after surgery. LESSONS: The experience can provide a basis use of MH-NRES and improve the ability of anesthesiologists to deal with intraoperative MH as well as increase the survival probability of patients.

Impact of hyperoxia on the gut during critical illnesses.

Molecular oxygen is typically delivered to patients via oxygen inhalation or extracorporeal membrane oxygenation (ECMO), potentially resulting in systemic hyperoxia from liberal oxygen inhalation or localized hyperoxia in the lower body from peripheral venoarterial (VA) ECMO. Consequently, this exposes the gastrointestinal tract to excessive oxygen levels. Hyperoxia can trigger organ damage due to the overproduction of reactive oxygen species and is associated with increased mortality. The gut and gut microbiome play pivotal roles in critical illnesses and even small variations in oxygen levels can have a dramatic influence on the physiology and ecology of gut microbes. Here, we reviewed the emerging preclinical evidence which highlights how excessive inhaled oxygen can provoke diffuse villous damage, barrier dysfunction in the gut, and gut dysbiosis. The hallmark of this dysbiosis includes the expansion of oxygen-tolerant pathogens (e.g., Enterobacteriaceae) and the depletion of beneficial oxygen-intolerant microbes (e.g., Muribaculaceae). Furthermore, we discussed potential impact of oxygen on the gut in various underlying critical illnesses involving inspiratory oxygen and peripheral VA-ECMO. Currently, the available findings in this area are somewhat controversial, and a consensus has not yet to be reached. It appears that targeting near-physiological oxygenation levels may offer a means to avoid hyperoxia-induced gut injury and hypoxia-induced mesenteric ischemia. However, the optimal oxygenation target may vary depending on special clinical conditions, including acute hypoxia in adults and neonates, as well as particular patients undergoing gastrointestinal surgery or VA-ECMO support. Last, we outlined the current challenges and the need for future studies in this area. Insights into this vital ongoing research can assist clinicians in optimizing oxygenation for critically ill patients.

Zinc Oxide Nanoparticles Exacerbate Epileptic Seizures by Modulating the TLR4-Autophagy Axis.

Background: Zinc oxide nanoparticles (ZnO NPs) has been widely used in various fields and has had an important impact on human public health. In addition, it inevitably damages human health, including neurological diseases. Therefore, this study explored the effect of ZnO NPs on epilepsy. Methods: The effect of ZnO NPs on epilepsy was observed by behavioral analysis. TLR4 expression and autophagy related pathways were detected by RNA-seq and Western blot. In addition, the cell types of autophagy were detected by immunofluorescence. Further, the electrophysiological changes of ZnO NPs induced autophagy were detected by whole-cell patch-clamp. Finally, the recovery experiment was carried out by TLR4 inhibitor (TAK-242). Results: We found that ZnO NPs enhanced epilepsy susceptibility and severity. Through RNA-seq analysis and Western blot, it was found that ZnO NPs affected the changes of TLR4 and autophagy related pathways. In addition, we found that ZnO NPs mainly affects autophagy of inhibitory neurons, resulting in excitation/inhibition imbalance. The autophagy and epileptic phenotypes were reversed with TAK-242. In general, ZnO NPs exacerbate epileptic seizures by modulating the TLR4-autophagy axis. Conclusion: ZnO NPs enhanced the susceptibility and severity of epilepsy. Mechanistically, ZnO NPs affected autophagy by changing the expression of TLR4. In particular, the ZnO NPs mainly affected the synaptic function of inhibitory neuron, leading to excitation/inhibition imbalances.

Molecular and Family Analyses of a Novel RHD1058G>C Allele in a Chinese RhD Population.

BACKGROUND: Rh(D) phenotype in a sample from a 19-year-old female patient showed weak positivity (1+). A follow-up sample was requested to further define the Rh(D) phenotype, her Rh(D) phenotype was tested by using another reagent, Rh(D) phenotype still showed weak reactivity (1+), RhCcEe phenotype was Ccee. METHODS: Seven samples from the family members of the proposita were received. The RhDCcEe phenotypes were typed by the microcolumn gel card and the unexpected antibodies were assayed by indirect anti-human globulin test (IAT). Genomic DNA was extracted from the blood sample and the novel RHD1058G>C allele was detected through an established sequence-specific primer PCR (PCR-SSP), RHD exons 1 - 10 were sequenced afterward by exon-specific amplification. The distribution of RHD1058G>C allele and RHD weak positive phenotype were investigated in the pedigrees. RESULTS: The unexpected antibodies all were negative in the family members. The novel RHD1058G>C allele was found in the proposita, her father, and grandfather. Five family members were detected serologically with the common Rh(D)-positive phenotypes either as homozygote of RHD/RHD or heterozygote of RHD/RHd. Two family members were detected as weak D phenotypes in accordance with the genotyping results by PCR-SSP, and both of them have a D1058Ce haplotype and a dce haplotype. One member, her father, was tested common Rh(D)-positive with D1058Ce haplotype and a Dce haplotype. CONCLUSIONS: These data allow us to describe the characteristics of the weak D phenotype with a novel c.RHD-1058G>C allele, which may be partial D and increase the risk of RHD alloantibody. The novel RHD1058G>C allele was inherited in three generations in a family rather than spontaneous mutation in an individual.

LncRNA MCM3AP-AS1 promotes chemoresistance in triple-negative breast cancer through the miR-524-5p/RBM39 axis.

Triple-negative breast cancer (TNBC) is the most lethal subtype of BC, with unfavorable treatment outcomes. Evidence suggests the engagement of lncRNA MCM3AP-AS1 in BC development. This study investigated the action of MCM3AP-AS1 in chemoresistance of TNBC cells. Drug-resistant TNBC cell lines SUM159PTR and MDA-MB-231R were constructed by exposure to increasing concentrations of doxorubicin/docetaxel (DOX/DXL). MCM3AP-AS1 and miR-524-5p expression levels were determined by RT-qPCR. RNA binding motif 39 (RBM39) level was measured using Western blot. Cell viability and apoptosis were assessed by CCK-8 assay and flow cytometry. The targeted binding of miR-524-5p with MCM3AP-AS1 or RBM39 was predicted by ECORI database and validated by dual-luciferase assays. The gain-and-loss of function assays were conducted in cells to investigate the interactions among MCM3AP-AS1, miR-524-5p, and RBM39. TNBC xenograft mouse models were established through subcutaneous injection of MCM3AP-AS1-silencing MDA-MB-231R cells and intraperitoneally administrated with DOX/DXL to verify the role of MCM3AP-AS1 in vivo. MCM3AP-AS1 was upregulated in drug-resistant TNBC cells, and MCM3AP-AS1 silencing could sensitize drug-resistant TNBC cells to chemotherapeutic drugs by promoting apoptosis. MCM3AP-AS1 targeted miR-524-5p. After DOX/DXL treatment, miR-524-5p inhibition partially reversed the effect of MCM3AP-AS1 silencing on inhibiting chemoresistance and promoting apoptosis of drug-resistant TNBC cells. miR-524-5p targeted RBM39. Silencing MCM3AP-AS1 promoted apoptosis via the miR-524-5p/RBM39 axis, thereby enhancing chemosensitivity of drug-resistant TNBC cells. MCM3AP-AS1 knockdown upregulated miR-524-5p, downregulated RBM39, and restrained tumor development in vivo. MCM3AP-AS1 silencing potentiates apoptosis of drug-resistant TNBC cells by upregulating miR-524-5p and downregulating RBM39, thereby suppressing chemoresistance in TNBC.

Diterpenoids from Torreya grandis and their cytotoxic activities.

Eight previously undescribed diterpenoids, along with eleven previously reported analogues, were obtained from the supercritical CO2 extracts of Torreya grandis aril. The structures of these compounds were elucidated based on HRESIMS, NMR, ECD, and single-crystal X-ray diffraction data. In the MTT assay, compound 18 exhibited significant inhibitory effects on two human colon cancer cell lines, HT-29 and HCT 116 cells, with IC50 values of 7.37 µM and 6.55 µM, respectively. It was found that compound 18 induced apoptosis and significantly inhibited the migration of HCT 116 colon cancer cells in a concentration-dependent manner.

Icariin has the potential to induce the differentiation of bone marrow mesenchymal stem cells into brown fat cells via PDE5A inhibition.

Background: Bone marrow mesenchymal stem cells (BMMSCs) possess the ability of adipogenic differentiation. Icariin (ICA) is a prenylated flavonol glycoside with diverse pharmacological activities and has been reported to promote osteogenic differentiation of BMMSCs. Nevertheless, the effects of ICA on BMMSC adipogenic differentiation into brown fat cells are still unclear. This study aimed to explore the effects and mechanistic basis of ICA on the differentiation of BMMSCs into brown fat cells. Methods: Oil Red-O staining assay was applied to detect the adipogenic differentiation of BMMSCs after induction. RT-qPCR and Western blot were conducted to detect the expression of lipogenic markers PPARγ and FABP4 as well as the brown fat biomarkers BMP7, PGC-1α, and UCP1 in BMMSCs. Moreover, phosphodiesterase-5A (PDE5A) expression in BMMSCs treated with ICA was measured by RT-qPCR and Western blot. Results: ICA promoted the adipogenic differentiation of BMMSCs and increased the expression levels of lipogenic markers PPARγ and FABP4 and the brown fat biomarkers BMP7, PGC-1α, and UCP1 during the adipogenic differentiation of BMMSCs. Furthermore, PDE5A was identified as a target of ICA, and its expression was reduced by ICA treatment. Moreover, PDE5A inhibition enhanced BMP7, PGC-1α, and UCP1 levels in BMMSCs. Additionally, overexpression of PDE5A notably reversed the effects of ICA in the differentiation of BMMSCs into brown fat cells. Conclusion: ICA induces the differentiation of BMMSCs into brown fat cells via PDE5A inhibition, highlighting the therapeutic value of ICA for treating obesity-related diseases.

Neuroprotective effect of chitosan oligosaccharide on alcohol-induced hippocampal injury using proteomic analysis.

Alcoholism is a serious public health problem, and the abuse of drinking seriously damages the health of people. Chitosan oligosaccharides (COSs) are small-molecule oligosaccharides with amino groups that have many unique properties. The neuroprotective effect of COS on alcohol-induced hippocampal injury in Sprague-Dawley (SD) rats was investigated. The discrimination ratio of the COS group in the Y-maze experiment was 59.3% higher than that of the ETOH group. Meanwhile, the discrimination index was less than 0 in the ETOH group but greater than 0 in the COS group during the object recognition test. The cells in the COS group were more tightly arranged than those in the ETOH group. Proteomics was used to identify differentially expressed proteins in the hippocampus. There were 27 differentially expressed proteins in the COS and ETOH group for further bioinformatic analysis. There are three enriched pathway categories, namely, primary immunodeficiency, hedgehog signaling, and sulfur relay system. Next, sonic hedgehog signaling pathway-related proteins were verified through western blotting. The protein expression level of ß-arrestin-2 in the COS group was 2.85 times higher than that in the ETOH group. This work may contribute to understanding the underlying mechanism of the neuroprotective effect of COS against alcohol-induced hippocampal injury in SD rats.

Effects of astaxanthin on depressive and sleep symptoms: A narrative mini-review.

Major depressive disorder (MDD) is a prevalent psychiatric condition that results in persistent feelings of sadness and loss of interest, imposing a significant economic burden on health systems and society. Impaired sleep is both a symptom and a risk factor for depression. Natural astaxanthin (AST), a carotenoid primarily derived from algae and aquatic animals, possesses multiple pharmacological properties such as anti-inflammatory, anti-apoptotic, and antioxidant stress effects. Prior research suggests that AST may have antidepressant properties. This mini-review highlights the potential mechanisms by which AST can prevent depression, providing novel insights into drug research for depression treatment. Specifically, this mechanism suggests that astaxanthin may improve sleep and thus potentially aid in the treatment of depression.

Identification of angiogenesis-related genes signature for predicting survival and its regulatory network in glioblastoma.

Glioblastoma (GBM) is notorious for malignant neovascularization that contributes to undesirable outcome. However, its mechanisms remain unclear. This study aimed to identify prognostic angiogenesis-related genes and the potential regulatory mechanisms in GBM. RNA-sequencing data of 173 GBM patients were obtained from the Cancer Genome Atlas (TCGA) database for screening differentially expressed genes (DEGs), differentially transcription factors (DETFs), and reverse phase protein array (RPPA) chips. Differentially expressed genes from angiogenesis-related gene set were extracted for univariate Cox regression analysis to identify prognostic differentially expressed angiogenesis-related genes (PDEARGs). A risk predicting model was constructed based on 9 PDEARGs, namely MARK1, ITGA5, NMD3, HEY1, COL6A1, DKK3, SERPINA5, NRP1, PLK2, ANXA1, SLIT2, and PDPN. Glioblastoma patients were stratified into high-risk and low-risk groups according to their risk scores. GSEA and GSVA were applied to explore the possible underlying GBM angiogenesis-related pathways. CIBERSORT was employed to identify immune infiltrates in GBM. The Pearson's correlation analysis was performed to evaluate the correlations among DETFs, PDEARGs, immune cells/functions, RPPA chips, and pathways. A regulatory network centered by three PDEARGs (ANXA1, COL6A1, and PDPN) was constructed to show the potential regulatory mechanisms. External cohort of 95 GBM patients by immunohistochemistry (IHC) assay demonstrated that ANXA1, COL6A1, and PDPN were significantly upregulated in tumor tissues of high-risk GBM patients. Single-cell RNA sequencing also validated malignant cells expressed high levels of the ANXA1, COL6A1, PDPN, and key DETF (WWTR1). Our PDEARG-based risk prediction model and regulatory network identified prognostic biomarkers and provided valuable insight into future studies on angiogenesis in GBM.

Exploring the predictive value of combined ultrasound parameters for spinal anesthesia-induced hypotension in cesarean section: a prospective observational study.

BACKGROUND: Prophylactic vasopressor infusion can effectively assist with fluid loading to prevent spinal anesthesia-induced hypotension. However, the ideal dose varies widely among individuals. We hypothesized that hypotension-susceptible patients requiring cesarean section (C-section) could be identified using combined ultrasound parameters to enable differentiated prophylactic medical interventions. METHODS: This prospective observational trial was carried out within a regional center hospital for women and children in Sichuan Province, China. Singleton pregnant women undergoing combined spinal-epidural anesthesia for elective C-sections were eligible. Women with contraindications to spinal anesthesia or medical comorbidities were excluded. Velocity time integral (VTI) and left ventricular end-diastolic area (LVEDA) in the supine and left lateral positions were measured on ultrasound before anesthesia. Stroke volume, cardiac output, and the percentage change (%) in each parameter between two positions were calculated. Vital signs and demographic data were recorded. Spinal anesthesia-induced hypotension was defined as a mean arterial pressure decrease of > 20% from baseline. The area under the receiver operating characteristic curve (AUROC) was used to analyze the associations of ultrasound measurements, vital signs, and demographic characteristics with spinal anesthesia-induced hypotension. This exploratory study did not have a predefined outcome; however, various parameter combinations were compared using the AUROC to determine which combined parameters had better predictive values. RESULTS: Patients were divided into the normotension (n = 31) and hypotension groups (n = 57). A combination of heart rate (HR), LVEDAs, and VTI% was significantly better at predicting hypotension than was HR (AUROC 0.827 vs. 0.707, P = 0.020) or LVEDAs (AUROC 0.827 vs. 0.711, P = 0.039) alone, but not significantly better than VTI% alone (AUROC 0.827 vs. 0.766, P = 0.098). CONCLUSION: The combined parameters of HR and LVEDAs with VTI% may predict spinal anesthesia-induced hypotension more precisely than the single parameters. Future research is necessary to determine whether this knowledge improves maternal and neonatal outcomes. TRIAL REGISTRATION: ChiCTR1900025191.

Study on the Intervention Mechanism of Cryptotanshinone on Human A2780 Ovarian Cancer Cell Line Using GC-MS-Based Cellular Metabolomics.

Cryptotanshinone (CT), an active component of the traditional Chinese medicine Salvia miltiorrhiza Bunge, exhibits a wide range of biological and pharmacological activities. Although the anticancer activity of CT is well known, the knowledge of its effect on the regulation of cancer cell metabolism is relatively new. The present study investigated the anticancer mechanism of CT in ovarian cancer with a focus on cancer metabolism. CCK8 assays, apoptosis assays, and cell cycle assays were conducted to reveal the growth-suppressive effect of CT on ovarian cancer A2780 cells. To explore the potential underlying mechanisms of CT, the changes in endogenous metabolites in A2780 cells before and after CT intervention were investigated using the gas chromatography-mass spectrometry (GC-MS) approach. A total of 28 important potential biomarkers underwent significant changes, mainly involving aminoacyl-tRNA biosynthesis, energy metabolism, and other pathways. Changes in the ATP and amino acid contents were verified with in vitro and in vivo experiments. Our results indicate that CT may exert an anti-ovarian cancer effect by inhibiting ATP production, promoting the protein catabolic process, and inhibiting protein synthesis, which may lead to cell cycle arrest and apoptosis.

Evaluation safety and efficacy of immune checkpoint blockers (ICB) and radiotherapy combination versus ICB in non-small cell lung cancer patients with recurrence or metastasis: A systematic review and meta-analysis.

BACKGROUND: Currently, immune checkpoint blockers (ICB) and radiotherapy (RT) combination therapy is broadly applied in non-small cell lung cancer (NSCLC) patients. However, meta-analysis about safety and efficacy of RT + ICB versus ICB has not yet been reported. To evaluate safety and efficacy of the combination therapy of ICB and RT in patients with recurrent or metastatic NSCLC and explore factors related to higher response rates, longer lifetime, and lower toxicity, meta-analysis of previous clinical data will be presented in this article. METHODS: A literature search on patients with recurrent or metastatic NSCLC treated with RT + ICB versus ICB was performed using the Cochrane Library, Embase and PubMed up to December 10, 2022. Suitable quality assessment checklists were selected corresponding to various types of research studies. Comparative and single-arm studies were analyzed using Stata 14.0. RESULTS: 10 comparative studies and 15 arms of combination therapy were included for this meta-analysis. RT significantly improved objective response rate (ORR), disease control rate (DCR), and overall survival (OS) and progression-free survival (PFS) of ICB (I-square value (I2 ) = 0.00%, odds ratio (OR) 1.28, 95% confidence interval (CI) 1.09-1.49, I2 = 0.00%, OR 1.12, 95% CI 1.00-1.25, I2 = 42.1%, OR 0.81, 95% CI 0.72-0.92, I2 = 34.5%, OR 0.80, and 95% CI 0.71-0.89, respectively). Toxicity between combination therapy and ICB monotherapy did not significantly differ in any grade or in ≥3 grade of tr-AEs (I2 = 0.00%, OR 1.05, 95% CI 0.91-1.22, I2 = 0.00%, OR 1.46, 95% CI 0.90-2.37, respectively). Subgroup analyses based on single-arm studies showed that applications of SRS/SBRT, PD-1 inhibitor, and administration of ICB after RT were conducive to a better DCR, longer OS and mild adverse events (heterogeneity between groups (HBG) all p < 0.05). CONCLUSION: RT can significantly improve ORR, DCR, OS, and PFS of ICB in patients with recurrent or metastatic NSCLC without increasing toxicity. PD-1 inhibitor following SRS/SBRT could be the best option to maximally benefit the patients.

Early changes in soluble intracellular adhesion molecule-1 as prognostic biomarkers to immune checkpoint inhibitor.

Serologic biomarker to predict clinical outcome is needed for immune checkpoint inhibitors (ICIs). We evaluated soluble intercellular adhesion molecules-1 (sICAM-1) as a predictor of response to ICIs treatment. Ninety-five patients with cancer treated with ICI were studied. The serum sICAM-1 levels of baseline, post two cycle therapy and end of therapy (EOT) were measured by enzyme-linked immunoassay. We randomly assigned the patients into the primary cohort (n = 47) and validation cohort (n = 48). Serum sICAM-1 post two cycle (277.7 ± 181.6 ng/mL) and EOT (403.9 ± 218.9 ng/mL) were significantly elevated compared to baseline (244.8 ± 153.8 ng/mL, p = 0.008 and p = 0.004, respectively). Early changes of sICAM-1 (ΔsICAM-1), deemed as sICAM-1 after two cycles minus baseline, were assessed. Following ICI treatments, responders had significantly lower ΔsICAM-1 compared with nonresponders in the primary cohort (p = 0.040) and the validation cohort (p = 0.026). High ΔsICAM-1 was strongly associated with inferior progression-free survival (PFS; (primary cohort: p = 0.001 and validation cohort: p = 0.002) and overall survival (OS; (primary cohort: p < 0.001 and validation cohort: p = 0.007). The ΔsICAM-1 remained independently associated with worse PFS and OS in the primary cohort and the validation cohort. Subgroup analysis indicated patients whose sICAM-1 significantly elevated had shorter PFS and OS in both anti-PD-1 and anti-PD-L1 treatment groups. Early change of serum sICAM-1 could be used to monitor and predict clinical benefit of ICI therapy in patients with solid cancer.

The effect of chronic endometritis and treatment on patients with unexplained infertility.

PURPOSE: This paper was mainly conducted to investigate the effect of chronic endometritis (CE) on the clinical outcome of patients with unexplained infertility. MATERIALS AND METHODS: 145 patients with unexplained infertility from the Reproductive Center of our hospital from January 2018 to December 2021 were selected as the unexplained infertility group. 42 patients with definite infertility causes were selected as the control group during the same period. Both groups of patients underwent hysteroscopy and immunohistochemical tests for CD38 and CD138. According to the results of hysteroscopy and immunohistochemistry, the incidence of CE between the two groups was analyzed. Patients with CE as CE group accepted oral antibiotic therapy for 14 days. Another 58 patients with unexplained infertility who did not undergo hysteroscopy and immunohistochemical tests for CD38 and CD138 were selected as the unexamined group. Both groups of patients were expected natural pregnancy. Follow-up lasted for 1 year, and the pregnant patients were followed up until delivery.The clinical pregnancy rate, spontaneous abortion rate and baby-carrying home rate of the two groups were compared. RESULTS: There were 75 patients with CE in the unexplained infertility group, and the prevalence rate was 51.7% (75/145). Compared with the control group (28.6%), the incidence of CE was significantly higher (P < 0.05). After treated with antibiotic treatment, the patients' clinical pregnancy rate was 61.3% (46/75) and baby-carrying home rate was 60% (45/75) in the CE group, which were higher than those in the unexamined group(43.1% & 36.2%) (P < 0.05), while the spontaneous abortion rate was 2.2% (1/46),which was lower than that in the unexamined group (16.0%) (P < 0.05). CONCLUSIONS: For patients with unexplained infertility, hysteroscopy combined with endometrial immunohistochemical detection of CD38 and CD138 should be performed in time to exclude CE. The clinical pregnancy outcome of CE patients can be significantly improved by antibiotic treatment.

Syntabulin regulates neuronal excitation/inhibition balance and epileptic seizures by transporting syntaxin 1B.

Epilepsy is a widespread neurological disorder affecting more than 65 million people, but the mechanisms of epilepsy remains unknown. Abnormal synaptic transmission has a crucial role in the occurrence and development of epilepsy. Here, we found that syntabulin, a neuronal transporter, was mainly localized in neurons, and its expression was increased in epileptic tissues. Knockdown of syntabulin increased susceptibility and severity of epilepsy, whereas overexpression of syntabulin had the opposite effect. Mechanistically, in the epileptic brain tissue, syntabulin mainly translocated syntaxin 1B (STX1B) rather than syntaxin 1A (STX1A) to the presynaptic membrane, which resulted in increased presynaptic transmitter release. Further studies showed that syntabulin had a more significant effect on presynaptic functionality of GABAergic activity over that of excitatory synapses and resulted in an excitation/inhibition (E/I) imbalance, thereby regulating the epileptic phenotype. In addition, we found that the increased expression of syntabulin in epileptic brain tissue was mainly regulated by transcription factor TFAP2A. In summary, syntabulin plays a protective role in epilepsy by maintaining a proper E/I balance in the hippocampus.

KCTD13-mediated ubiquitination and degradation of GluN1 regulates excitatory synaptic transmission and seizure susceptibility.

Temporal lobe epilepsy (TLE) is the most common and severe form of epilepsy in adults; however, its underlying pathomechanisms remain elusive. Dysregulation of ubiquitination is increasingly recognized to contribute to the development and maintenance of epilepsy. Herein, we observed for the first time that potassium channel tetramerization domain containing 13 (KCTD13) protein, a substrate-specific adapter for cullin3-based E3 ubiquitin ligase, was markedly down-regulated in the brain tissue of patients with TLE. In a TLE mouse model, the protein expression of KCTD13 dynamically changed during epileptogenesis. Knockdown of KCTD13 in the mouse hippocampus significantly enhanced seizure susceptibility and severity, whereas overexpression of KCTD13 showed the opposite effect. Mechanistically, GluN1, an obligatory subunit of N-methyl-D-aspartic acid receptors (NMDARs), was identified as a potential substrate protein of KCTD13. Further investigation revealed that KCTD13 facilitates lysine-48-linked polyubiquitination of GluN1 and its degradation through the ubiquitin-proteasome pathway. Besides, the lysine residue 860 of GluN1 is the main ubiquitin site. Importantly, dysregulation of KCTD13 affected membrane expression of glutamate receptors and impaired glutamate synaptic transmission. Systemic administration of the NMDAR inhibitor memantine significantly rescued the epileptic phenotype aggravated by KCTD13 knockdown. In conclusion, our results demonstrated an unrecognized pathway of KCTD13-GluN1 in epilepsy, suggesting KCTD13 as a potential neuroprotective therapeutic target for epilepsy.

Case report: NUDT15 polymorphism and severe azathioprine-induced myelosuppression in a young Chinese female with systematic lupus erythematosus: a case analysis and literature review.

Azathioprine is clinically used as an immunosuppressant for treating autoimmune diseases. However it has narrow therapeutic indices due to frequent myelosuppression. Polymorphic variants of genes coding for thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X motif 15 (NUDT15) are critical determinants of AZA intolerance, and the differences in frequencies of the two genetic variants exist among people of different ethnicities. Most reports regarding NUDT15 variant, AZA-induced myelosuppression occurred in patients with inflammatory bowel disease and acute lymphoblastic leukemia. Moreover, detailed clinical characteristics were not frequently reported. Here we present the case of a young Chinese female with the NUDT15 c.415C>T (rs116855232, TT) homozygous variant and wild-type TPMT*2 (rs1800462), TPMT*3B (rs1800460), and TPMT*3C (rs1142345) who received high doses of AZA (2.3 mg/kg/d) for systematic lupus erythematosus and had not been told to undergo routine blood cell counts during AZA ingestion. The patient had suffered from severe AZA-induced myelosuppression and alopecia. Moreover, dynamic changes in blood cell counts and responses to treatment were observed. We also conducted a systematic review of published case reports of patients exclusively with NUDT15 c.415C>T homozygous or heterozygous variants to review the characteristics of dynamic changes in blood cells so as to provide reference information for clinical treatment.

Activation of TLR7-mediated autophagy increases epileptic susceptibility via reduced KIF5A-dependent GABAA receptor transport in a murine model.

The pathophysiological mechanisms underlying epileptogenesis are poorly understood but are considered to actively involve an imbalance between excitatory and inhibitory synaptic transmission. Excessive activation of autophagy, a cellular pathway that leads to the removal of proteins, is known to aggravate the disease. Toll-like receptor (TLR) 7 is an innate immune receptor that regulates autophagy in infectious and noninfectious diseases. However, the relationship between TLR7, autophagy, and synaptic transmission during epileptogenesis remains unclear. We found that TLR7 was activated in neurons in the early stage of epileptogenesis. TLR7 knockout significantly suppressed seizure susceptibility and neuronal excitability. Furthermore, activation of TLR7 induced autophagy and decreased the expression of kinesin family member 5 A (KIF5A), which influenced interactions with γ-aminobutyric acid type A receptor (GABAAR)-associated protein and GABAARß2/3, thus producing abnormal GABAAR-mediated postsynaptic transmission. Our results indicated that TLR7 is an important factor in regulating epileptogenesis, suggesting a possible therapeutic target for epilepsy.